Methods of forming microparticle coated medical device

ABSTRACT

A drug-loaded microparticle is applied to a medical device for subsequent application to biological tissues. A method of formulating a drug-loaded microparticle and applying it to the surface of a medical device, such as a stent, is disclosed. The drug-loaded microparticle is formulated by combining a drug with various chemical solutions. Specified sizes of the microparticles and amounts of drug(s) contained within the microparticles may be varied by altering the proportions of the chemicals/solutions. In addition to various drugs, therapeutic substances and radioactive isotopes may also be loaded into the microparticles. The drug-loaded microparticle are suspended in a polymer solution forming a polymer matrix. The polymer matrix may be applied to the entire surface or only selected portions of the medical device via dipping, spraying or combinations thereof.

CROSS REFERENCE

This is a divisional application of application Ser. No. 09/851,877,filed on May 9, 2001, and which issued as U.S. Pat. No. 6,656,506 onDec. 2, 2003.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a medical device for use in tissue andorgan treatment and, in particular, to drug-loaded microparticlesembedded within a matrix and applied to the medical device.

2. Related Art

A variety of surgical procedures and medical devices are currently usedto relieve intraluminal constrictions caused by disease or tissuetrauma. An example of one such procedure is percutaneous transluminalcoronary angioplasty (PTCA). PTCA is a catheter-based technique wherebya balloon catheter is inserted into a blocked or narrowed coronary lumenof the patient. Once the balloon is positioned at the blocked lumen ortarget site, the balloon is inflated causing dilation of the lumen. Thecatheter is then removed from the target site thereby allowing blood tofreely flow through the unrestricted lumen.

Although PTCA and related procedures aid in alleviating intraluminalconstrictions, such constrictions or blockages reoccur in many cases.The cause of these recurring obstructions, termed restenosis, is due tothe body's immune system responding to the trauma of the surgicalprocedure. As a result, the PTCA procedure may need to be repeated torepair the damaged lumen.

Stents or drug therapies, either alone or in combination with the PTCAprocedure, are often used to avoid or mitigate the effects of restenosisat the surgical site. In general, stents are small, cylindrical deviceswhose structure serves to create or maintain an unobstructed openingwithin a lumen. The stents are typically made of stainless steel or amemory-responsive metal, such as Nitinol™ and are delivered to thetarget site via a balloon catheter. Although the stents are effective inopening the stenotic lumen, the foreign material and structure of thestents themselves may exacerbate the occurrence of restenosis orthrombosis.

Drugs or similar agents that limit or dissolve plaque and clots are usedto reduce, or in some cases eliminate, the incidence of restenosis andthrombosis. Since the drugs are applied systemically to the patient,they are absorbed not only by the tissues at the target site, but by allareas of the body. As such, one drawback associated with the systemicapplication of drugs is that areas of the body not needing treatment arealso affected. To provide more site-specific treatment, stents arefrequently used as a means of delivering the drugs exclusively to thetarget site. By positioning the stent at the target site, the drugs canbe applied directly to the area of the lumen requiring therapy ordiagnosis.

In addition to the benefit of site-specific treatment, drug-loadedstents also offer long-term treatment and/or diagnostic capabilities.These stents include a biodegradable or absorbable polymer suspensionthat is saturated with a particular drug. In use, the stent ispositioned at the target site and retained at that location either for apredefined period or permanently. The polymer suspension releases thedrug into the surrounding tissue at a controlled rate based upon thechemical and/or biological composition of the polymer and drug.

The above-described devices and methods for treatment of restenosis andthrombosis, and other similar conditions not specifically described,offer many advantages to potential users. However, it has beendiscovered that such devices and methods may be deficient in theircurrent drug-loading and drug-delivery characteristics. In particular,the amount or volume of drug capable of being delivered to the targetsite may be insufficient due to the limited surface area of the stent.In addition, drug release rates may also be inadequate since the rate atwhich the drug is released or delivered to the target site is a functionof the chemical and/or biological properties of the polymer in which thedrug is embedded.

SUMMARY

In view of the above, it is apparent that there is a need to provide adrug delivery device offering increased drug loading capabilities formedical devices and improved drug release rates. It is also desirablethat the drug-delivery device allows one or more drugs to be releasedfrom the medical device to the target site. In addition, it is preferredthat the device features enable one or more drugs to be released atvariable and/or independent rates. There is also a need to provide amethod of manufacturing such an improved drug delivery device that isconvenient, efficient and cost effective.

In accordance with various aspects of the present invention, a smallparticle, such as a micro- and/or nanoparticle (hereinafter referred tointerchangeably as “microparticle”), is formed and loaded with a drug.The drug-loaded microparticle is formulated by combining a drug withvarious chemical solutions. In one embodiment, a microparticle can beformed by adding a drug-loaded solution containing a photoinitiator intoa relatively inert bath. Light or similar energy is applied to thesolution in the bath causing a photo-chemical reaction that produces oneor more microparticles. In another embodiment, the drug-loaded solutionis combined with a cross-linker solution and vigorously vortexed in ainert bath. The agitation together with the chemical reaction producesone or more microparticles. Specified sizes of the microparticles andamounts of drug(s) contained within the microparticles may be varied byaltering the proportions of the above chemicals/solutions and by varyingthe process parameters during mixing. In addition to various drugs,therapeutic substances and radioactive isotopes may also be loaded intothe microparticles.

Another aspect of the present invention is a method of applying adrug-loaded microparticle onto a medical device. A microparticle can beformed and loaded with one or more drugs, as described above. Thedrug-loaded microparticle is suspended in a polymer solution forming apolymer matrix. In one embodiment, the medical device is dipped in thepolymer matrix so that a coating of the polymer matrix having arelatively smooth surface texture is applied over the entire surface ofthe medical device. In another embodiment, the entire surface of themedical device is spray coated with the polymer matrix. In yet anotherembodiment, only select portions of the medical device are coated withone or more polymer matrices.

Embodiments of the medical device make possible site specific treatmenttherapies. Coating different portions of an implantable medical device,with the disclosed microparticles loaded with various drugsadvantageously allows site-specific treatment of discrete sections ofthe patient's lumen. In addition, by embedding the drug-loadedmicroparticle in a polymer, the resulting matrix can increase ordecrease the release rate of the drug from the microparticle, dependingon the type of polymer used. As such, drug release rates and thereby,for example, long term treatment or diagnostic capabilities, can becontrolled. Moreover, the drugs can be suspended in a tissue-compatiblepolymer, such as silicone, polyurethane, polyvinyl alcohol,polyethylene, polyesters, swellable hydrogels, hyaluronate, variouscopolymers and blended mixtures thereof. Accordingly, a very selectivecushioning effect can be attained.

BRIEF DESCRIPTION OF THE DRAWINGS

The features of the described embodiments are specifically set forth inthe appended claims. However, embodiments relating to both structure andmethod of operation are best understood by referring to the followingdescription and accompanying drawings, in which similar parts areidentified by like reference numerals.

FIG. 1 is a side view of a drug-loaded medical device, e.g. stent, inaccordance with an embodiment of the present invention;

FIG. 2 is a cross-sectional view of a drug-coated elongated element inaccordance with an embodiment of the present invention; and

FIG. 3 illustrates a medical device inserted into the lumen of a patientin accordance with an embodiment of the present invention.

DETAILED DESCRIPTION

The term “drug(s),” as used herein, refers to all therapeutic agents,diagnostic agents/reagents and other similar chemical/biological agents,including combinations thereof, used to treat and/or diagnoserestenosis, thrombosis and related conditions. Examples of various drugsor agents commonly used include heparin, hirudin, antithrombogenicagents, steroids, ibuprofen, antimicrobials, antibiotics, tissue plasmaactivators, monoclonal antibodies, and antifibrosis agents.

A variety of drug classes and therapeutic substances may be used inaccordance with the present disclosure. For example, therapeuticsubstances or agents may include, but are not limited to,antineoplastic, antimitotic, antiinflammatory, antiplatelet,anticoagulant, antifibrin, antithrombin, antiproliferative, antibiotic,antioxidant, and antiallergic substances as well as combinationsthereof. Examples of such antineoplastics and/or antimitotics includepaclitaxel (e.g. TAXOL® by Bristol-Myers Squibb Co., Stamford, Conn.),docetaxel (e.g. Taxotere®, from Aventis S. A., Frankfurt, Germany),methotrexate, azathioprine, vincristine, vinblastine, fluorouracil,actinomycin-D, doxorubicin hydrochloride (e.g. Adriamycin® fromPharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g. Mutamycin® fromBristol-Myers Squibb Co., Stamford, Conn.). Examples of suchantiplatelets, anticoagulants, antifibrin, and antithrombins includesodium heparin, low molecular weight heparins, heparinoids, hirudin,argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, and thrombininhibitors such as Angiomax™ (Biogen, Inc., Cambridge, Mass.). Examplesof such cytostatic or antiproliferative agents include angiopeptin,angiotensin converting enzyme inhibitors such as captopril (e.g.,Capoten® and Capozide® from Bristol-Myers Squibb Co., Stamford, Conn.),cilazapril or lisinopril (e.g. Prinivil® and Prinzide® from Merck & Co.,Inc., Whitehouse Station, N.J.), calcium channel blockers (such asnifedipine), colchicine, fibroblast growth factor (FGF) antagonists,fish oil (omega 3-fatty acid), histamine antagonists, lovastatin (aninhibitor of HMG-CoA reductase, a cholesterol lowering drug, brand nameMevacor® from Merck & Co., Inc., Whitehouse Station, N.J.), monoclonalantibodies (such as those specific for Platelet-Derived Growth Factor(PDGF) receptors), nitroprusside, phosphodiesterase inhibitors,prostaglandin inhibitors, suramin, serotonin blockers, steroids,thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), andnitric oxide. An example of an antiallergic agent is permirolastpotassium. Other therapeutic substances or agents which may beappropriate include alpha-interferon, genetically engineered epithelialcells, and dexamethasone.

While the above listed substances or agents are well known forpreventative and therapeutic utility, the substances are listed by wayof example and are not meant to be limiting. Other therapeuticsubstances which are currently available or that may be developed in thefuture are equally applicable. The treatment of patients using the abovementioned medicines is well-known to those of ordinary skill in the art.

FIG. 1 illustrates a drug-loaded medical device 10. Medical device canbe any suitable medical device or prosthesis including, but not limitedto, balloons, stents coverings, vascular grafts, and other implantabledevices. For convenience and ease of comprehension, with no intent tolimit the invention thereby, medical device 10 referenced in the textand figures of the present disclosure is an implantable stent.

As shown in FIG. 1, stent 10 includes one or more elongated elements 12that are formed into a generally cylindrical or tubular shape having afirst end 14 and a second end 16. The shape of the preformed elongatedelements 12 may be straight, sinusoidal, V-shaped, or any other of avariety of patterns and shapes not disclosed herein. In addition, one ormore interconnecting elements (not shown) may also be included toconnect adjacent elongated elements 12 and increase the structuralintegrity of stent 10. As with the elongated elements 12, theinterconnecting elements may also have a variety of shapes and patternsincluding, but not limited to, circular, oval, straight, curved, and thelike.

The elongated elements 12 and interconnecting elements of stent 10 areconfigured to allow stent 10 to easily expand and contract, therebyfacilitating placement of stent 10 into an insertion device and,ultimately, a lumen of the body. To further enhance stent 10flexibility, these components are typically fabricated from a metallicmaterial or alloy, such as stainless steel, Nitinol™, tantalum, or othersimilar materials and/or combinations of such materials. The diameter ofeach elongated element 12 is typically within the range of approximately3.9×10⁻⁴ inch (0.001 cm) to 1.18×10⁻³ inch (0.003 cm). Similarly, thediameter for each interconnecting element is approximately within therange of 3.9×10⁻⁴ inch (0.001 cm) to 1.18×10⁻³ inch (0.003 cm). Overallstent 10 diameter and length is approximately within the range of0.1378±0.0394 inch (0.35±0.1 cm) and 0.5118±0.1969 inch (1.3±0.5 cm),respectively. The particular configuration of stent 10, such as choiceof materials, size, structural characteristics, and the like, may varybased upon the location of the lesion, type of lesion and lumendimensions of the target area.

Referring to the embodiment of FIG. 2, to aid in the treatment and/ordiagnosis of various conditions affecting the lumen, the entire surfaceof stent 10 can be coated with a polymer solution 18, which includes asuspension of drug-loaded microparticles 20, such as microspheres and/ornanospheres. It should be understood that the microparticles are notlimited to spheres and thus may have any shape and remain within thescope of the invention.

In this embodiment, the drug(s) remain suspended in the polymer matrixuntil stent 10 is deployed to the target site. When the surface 22 ofstent 10 engages the wall 24 of the lumen 26, as shown in FIG. 3, thedrug(s) disseminate from the polymer matrix (not shown) at a controlledrelease-rate. The drug(s) are absorbed into the tissue of the walls 24of the lumen 26 that are in contact with stent 10.

FIG. 2 shows a detailed cross-sectional portion of an elongated element12. Various methods can be employed to formulate and drug-load themicroparticles 20. The embodiments of the composition of drug-loadedmicroparticles 20 can be prepared by conventional methods where allcomponents are combined then blended. In accordance with one embodiment,microparticles 20 can be prepared using a predetermined amount of apolymer or a prepolymer that is added to a predetermined amount of asolvent or a combination of solvents. The solvent is mutually compatiblewith the polymer and is capable of placing the polymer into solution atthe concentration desired in the solution. Useful solvents can expandthe chains of the polymer for maximum interaction with the surface ofthe medical device, such as a metallic surface of a stent. Examples ofsolvents can include, but are not limited to, dimethylsulfoxide (DMSO),Dimethyl Acetamide (DMAC), chloroform, acetone, water (buffered saline),xylene, acetone, methanol, ethanol, 1-propanol, tetrahydrofuran,1-butanone, dimethylformamide, dimethylacetamide, cyclohexanone, ethylacetate, methylethylketone, propylene glycol monomethylether,isopropanol, N-methyl pyrrolidinone, toluene and mixtures thereof.

Microparticles 20 can be prepared in ambient pressure and underanhydrous atmosphere. If necessary, a free radical or UV initiator canbe added to microparticles 20 for initiating the curing or cross-linkingof the prepolymer. Heating and stirring and/or mixing can be employed toeffect dissolution of the polymer into the solvent.

By way of example, and not limitation, the polymer can comprise fromabout 0.1% to about 35%, more narrowly about 2% to about 20% by weightof the total weight of the total solution, and the solvent can comprisefrom about 65% to about 99.9%, more narrowly about 80% to about 98% byweight, of the total weight of the total solution. A specific weightratio is dependent on factors such as the material from which theimplantable device is made and the geometrical structure of the device.

Sufficient amounts of an active ingredient are dispersed or dissolved inmicroparticles 20. The active ingredient should be in solution orsuspension. If the active ingredient is not completely soluble in thecomposition, operations including mixing, stirring, and/or agitation canbe employed to effect homogeneity. The active ingredient may be added sothat the dispersion is in fine particles. The mixing of the activeingredient can be conducted in an anhydrous atmosphere, at ambientpressure, and at room temperature. In one embodiment, the activeingredient can minimize or inhibit the progression of neointimalhyperplasia. More specifically, the active ingredient is aimed atinhibiting abnormal or inappropriate migration and/or proliferation ofsmooth muscle cells and activation of inflammatory cells and platelets.

The following examples illustrate various drug-loading and microparticleformulation techniques, but do not limit possible techniques within thescope of the present invention. Note that “w/w” is an abbreviation for“by weight,” used in chemistry and pharmacology to describe theconcentration of a substance in a mixture or solution. For example, 25%w/w means that the mass of the substance is 25% of the total mass of thesolution or mixture.

EXAMPLE 1

A first solution is formulated using 25% w/w Polyethylene glycoldiacrylate (PEGDA) dissolved in water. A water soluble drug, such asdexamethasone, is added at 5% w/w into the first solution, forming asecond, PEGDA-Dexamethasone, solution. A third solution is formulatedusing 10% w/w 2,2, dimethoxy 2 phenyl acetophenone solution dissolved invinyl pyrrolidone (VP) monomer. This third solution is the curing agentor photoinitiator solution. A final solution is formulated by adding 1mL of the initiator solution per 9 mL of the PEGDA-Dexamethasonesolution.

The process of fabricating a single microparticle 20 involves adding adrop of the final solution, using a 10 micro-liter pipette, into aviscous mineral oil or silicone oil bath. After adding the drop ofsolution to the bath, a 360 nm wavelength black ray UV lamp is used tocure the spherical droplet suspended in the bath. This results in acrosslinked, swollen PEGDA particle containing dexamethasone. Themicroparticle 20 is left to settle to the bottom of the vial containingthe oil bath. The above process is repeated until the desired quantityof microparticles 20 is formed. The oil phase is then decanted off andthe particles 20 are washed in a solvent, such as acetone, to remove thepresence of any remaining oil.

EXAMPLE 2

A first solution is formulated using 25% w/w PEGDA dissolved indeionized water. Actinomycin-D (Ac/D) is added at 5% w/w into the firstsolution, forming a second solution comprising a suspension of Ac/D inthe PEGDA solution. A third (curing agent/photoinitiator) solution isformulated using 10% w/w 2,2, dimethoxy 2 phenyl acetophenone solutiondissolved in VP monomer. A final solution is formulated by adding 1 mLof the initiator solution per 9 mL of the PEGDA-Ac/D suspension.

The process of fabricating a single microparticle 20 involves adding adrop of the final solution, using a 10 micro-liter pipette, into aviscous mineral oil or silicone oil bath. After adding the drop ofsolution to the bath, a 360 nm wavelength black ray UV lamp is used tocure the spherical droplet suspended in the bath. This results in acrosslinked, swollen PEGDA particle containing Ac/D. The microparticle20 is left to settle to the bottom of the vial containing the oil bath.The above process is repeated until the desired quantity ofmicroparticles 20 is formed. The oil phase is then decanted off and theparticles 20 are washed in a solvent, such as acetone, to remove thepresence of any remaining oil.

EXAMPLE 3

A first solution is formulated using 25% w/w PEGDA dissolved indeionized water. Ac/D and dexamethasone are each added at 5% w/w intothe first solution, forming a second solution comprising a suspension ofAc/D and a solution of dexamethasone in the PEGDA solution. A third(curing agent/photoinitiator) solution is formulated using 10% w/w 2,2,dimethoxy 2 phenyl acetophenone solution dissolved in VP monomer. Afinal solution is formulated by adding 1 mL of the initiator solutionper 9 mL of the PEGDA-Ac/D suspension.

The final solution is added into a viscous mineral oil or silicone oiland vortexed vigorously. After the water-in-oil emulsion is formed, a360 nm wavelength black ray UV lamp is used to cure the sphericaldroplets suspended in the bath. This results in crosslinked, swollenPEGDA particles containing Ac/D. The microparticles 20 are left tosettle to the bottom of the vial containing the oil bath. The oil phaseis then decanted off and the particles 20 are washed in a solvent, suchas acetone, to remove the presence of any remaining oil.

EXAMPLE 4

A first solution is formulated using 25% w/w VP dissolved in deionizedwater. PEGDA, having a molecular weight of 1000, is added at 8% w/w intothe first solution, together with 5% w/w dexamethasone, forming a secondsolution comprising a suspension of PEGDA-dexamethasone in the VPsolution. A third (curing agent/photoinitiator) solution is formulatedusing 10% w/w 2,2, dimethoxy 2 phenyl acetophenone solution dissolved inVP monomer. A final solution is formulated by adding 1 mL of theinitiator solution per 9 mL of the VP-Dexamethasone suspension.

The process of fabricating a single microparticle 20 involves adding adrop of the final solution, using a 10 micro-liter pipette, into aviscous mineral oil or silicone oil bath. After adding the drop ofsolution to the bath, a 360 nm wavelength black ray UV lamp is used tocure the spherical droplet suspended in the bath. This results in acrosslinked, swollen VP particle containing Dexamethasone. Themicroparticle 20 is left to settle to the bottom of the vial containingthe oil bath. The above process is repeated until the desired quantityof microparticles 20 is formed. The oil phase is then decanted off andthe particles 20 are washed in a solvent, such as acetone, to remove thepresence of any remaining oil.

EXAMPLE 5

A first solution is formulated using 15% w/w VP dissolved in deionizedwater. PEGDA, having a molecular weight of 1000, is added at 15% w/winto the first solution. In addition, Ac/D is also added at 5% w/w,forming a second solution comprising a suspension of PEGDA and Ac/D inthe VP solution. A third (curing agent/photoinitiator) solution isformulated using 10% w/w 2,2, dimethoxy 2 phenyl acetophenone solutiondissolved in VP monomer. A final solution is formulated by adding 1 mLof the initiator solution per 9 mL of the PEGDA/Ac/D-VP suspension.

The final solution is added into a viscous mineral oil or silicone oiland vortexed vigorously. After the water-in-oil emulsion is formed, a360 nm wavelength black ray UV lamp is used to cure the sphericaldroplets suspended in the bath. This results in crosslinked, swollenPEGDA particles containing Ac/D. The microparticles 20 are left tosettle to the bottom of the vial containing the oil bath. The oil phaseis then decanted off and the particles 20 are washed in a solvent, suchas acetone, to remove the presence of any remaining oil.

EXAMPLE 6

A first solution is formulated using 10% w/w Poly Alginate (PAIg)dissolved in deionized water. Ac/D is added at 5% w/w into the firstsolution, forming a second solution comprising a suspension of Ac/D inthe PAIg solution. A third solution is formulated using 10% w/w Calciumchloride solution dissolved in deionized water. This third solution isthe curing agent or cross-linker solution.

The Ac/D-PAIg suspension is added into the cross-linker solution andvortexed vigorously. After the divalent ion cross-linked Alginateparticles are formed, the particles 20 are left to settle to the bottomof the vial containing the cross-linker solution. The cross-linker phaseis decanted off and the particles 20 are then washed in deionized water.

EXAMPLE 7

A first solution is formed by dissolving 10% w/v cellulose acetatephthalate (CAP), available from Schutz & Co., Germany, in a solvent,such as acetone. Note that “w/v” is an abbreviation for “weight byvolume,” a phrase used in chemistry and pharmacology to describe theconcentration of a substance in a mixture or solution. The weight byvolume is the mass (in grams) of the substance dissolved in or mixedwith 100 milliliters of solution or mixture. For example, theconcentration of CAP in a solvent, such as acetone, is 0.10% w/v,meaning that there is 0.10 gram of CAP per 100 milliliters of acetone.Thus 1% w/v is equal to 1 gram per deciliter (g/dL) or 10 grams perliter.

A second solution is formed by combining 100 mL of liquid paraffin (orother similar mixture of hydrocarbons) with 1% w/v Span™ 80 in a 400 mLbeaker. This solution is then agitated at 400 rpm using a 3-bladedstirrer (having a 5 cm diameter) connected to a stirring motor (e.g.,Tecmatic™ SD2).

One gram of Ac/D is dissolved in 20 mL of the first solution. Thissolution is then poured into the second solution, forming a finalsolution. Evaporation of the solvent from the final solution proceedsfor 24 hours at 30° C., producing residual microparticles 20 at thebottom of the beaker. The microparticles 20 are collected in a Büchner,or equivalent, filter and washed in 50 mL of ether. The microparticles20 are then allowed to dry at room temperature for 24 hours.

EXAMPLE 8

A first solution is formed by dissolving 10% w/v cellulose acetatephthalate (CAP), available from Schutz & Co., Germany, in a solvent,such as acetone. A second solution is formed by combining 100 mL ofliquid paraffin with 1% w/v Span 80 in a 400 mL beaker. This solution isthen agitated at 400 rpm using a 3-bladed stirrer (having a 5 cmdiameter) connected to a stirring motor (e.g., Tecmatic SD2).

One gram of Trapidil is dissolved in 20 mL of the first solution. Thismixture is then poured into the second solution. Evaporation of thesolvent from the mixture/solution proceeds for 24 hours at 30° C.,producing residual microparticles 20 at the bottom of the beaker. Themicroparticles 20 are collected in a Buchner, or equivalent, filter andwashed in 50 mL of ether. The microparticles 20 are then allowed to dryat room temperature for 24 hours.

The above-described formulation examples are specific to drug-loadedmicroparticles 20. Other materials, such as PEG-gels, PLA (polylacticacid), PCL (poly caprolactone), and the like, may also be used toformulate drug-loadable microparticles 20 using similar methods to thosedescribed above. Further, by modifying the pipette/dropper size orvortex speed, microparticles 20 of varying sizes may be formed. Smalleror larger sized microparticles 20 may be preferred to more accuratelycontrol drug volumes and duration of release rates.

In some embodiments, a second drug can be applied in the matrix polymer,such as EVAL. PEGDA hydrogel nanoparticles can be combined with otherdrug loaded nanoparticles to obtain additional effects, such as acushioning effect.

In addition to drugs, radioactive isotopes may also be loaded into themicroparticles 20, utilizing relatively similar formulation techniques.Examples of radioactive isotopes include, but are not limited to, ³²P,^(55,56,57)Co, ⁵²Mg, and ⁵⁵Fe. In one embodiment, nano-sizedgold-particles containing one or multiple radioisotopes are used tocreate a radiopaque/radiotherapy stent that is easily tracked through orlocated within the body of the patient.

To increase overall drug-loading on stent 10, the drug-loadedmicroparticles 20, shown in FIG. 2, are coated onto the entire surfaceof stent 10 with a biocompatible polymer solution 18. Any suitablepolymer solutions 18 can be used, such as low-density polyethylene, poly(ethylene glycol) and other similar solutions, such as polycaprolactone,ethylene vinyl acetate, polyvinyl alcohol and the like. In oneembodiment, the polymer solution 18 can be ethylene vinyl alcohol, whichis functionally a very suitable choice of polymer. Ethylene vinylalcohol copolymer, commonly known by the generic name EVOH or by thetrade name EVAL®, refers to copolymers including residues of bothethylene and vinyl alcohol monomers. One of ordinary skill in the artunderstands that ethylene vinyl alcohol copolymer may also be aterpolymer so as to include small amounts of additional monomers, forexample less than about five (5) mole percentage of styrenes, propylene,or other suitable monomers. In a useful embodiment, the copolymercomprises a mole percent of ethylene of from about 27% to about 47%.Typically, 44 mole percent ethylene is suitable. Ethylene vinyl alcoholcopolymers are available commercially from companies such as AldrichChemical Company, Milwaukee, Wis., or EVOH Company of America, Lisle,Ill., or can be prepared by conventional polymerization procedures thatare well known to one of ordinary skill in the art. The copolymerpossesses good adhesive qualities to the surface of stent 10,particularly stainless steel surfaces, and has illustrated the abilityto expand with stent 10 without any significant detachment of thecopolymer from the surface of stent 10.

If polymer solution 18 is used with a solvent, the solvent should bemutually compatible with polymer solution 18 and should be capable ofplacing polymer solution 18 into solution at the concentration desiredin the solution. Useful solvents should also be able to expand thechains of the polymer for maximum interaction with the surface of thedevice, such as the metallic surface of stent 10. Examples of solventcan include, but are not limited to, dimethylsulfoxide (DMSO),chloroform, acetone, water (buffered saline), xylene, acetone, methanol,ethanol, 1-propanol, tetrahydrofuran, 1-butanone, dimethylformamide,dimethylacetamide, cyclohexanone, ethyl acetate, methylethylketone,propylene glycol monomethylether, isopropanol, N-methyl pyrrolidinone,toluene and mixtures thereof.

A suitable fluid having a high capillary permeation can be added topolymer solution 18 to enhance the wetting for a more uniform coatingapplication. The wetting fluid, typically, should have a viscosity notgreater than about 50 centipoise, narrowly about 0.3 to about 5centipoise, more narrowly about 0.4 to about 2.5 centipoise. The wettingfluid should be mutually compatible with polymer solution 18 and thesolvent and should not precipitate polymer solution 18. The wettingfluid can also act as the solvent. Useful examples of the wetting fluidinclude, but are not limited to, tetrahydrofuran (THF),dimethylformamide (DMF), 1-butanol, n-butyl acetate, dimethyl acetamide(DMAC), and mixtures and combinations thereof.

In accordance with another embodiment, a fluid can be added to thecomposition to enhance the wetting of the composition for a more uniformcoating application. To enhance the wetting of the composition, asuitable fluid typically has a high capillary permeation. Capillarypermeation or wetting is the movement of a fluid on a solid substratedriven by interfacial energetics. The wetting fluid should be mutuallycompatible with the polymer and the solvent and should not precipitatethe polymer. The wetting fluid can also act as the solvent. Usefulexamples of the wetting fluid include, but are not limited to,tetrahydrofuran (THF), dimethylformamide (DMF), 1-butanol, n-butylacetate, dimethyl acetamide (DMAC), and mixtures and combinationsthereof.

By way of example and not limitation, the polymer can comprise fromabout 0.1% to about 35%, more narrowly from about 2% to about 20% byweight of the total weight of the composition; the solvent can comprisefrom about 19.9% to about 98.9%, more narrowly from about 58% to about84% by weight of the total weight of the composition; the wetting fluidcan comprise from about 1% to about 80%, more narrowly from about 5% toabout 40% by weight of the total weight of the composition. The specificweight ratio of the wetting fluid depends on the type of wetting fluidemployed and type of and the weight ratio of the polymer and thesolvent. More particularly, tetrahydrofuran used as the wetting fluidcan comprise, for example, from about 1% to about 44%, more narrowlyabout 21% by weight of the total weight of the solution.Dimethylformamide used as the wetting fluid can comprise, for example,from about 1% to about 80%, more narrowly about 8% by weight of thetotal weight of the solution. One-butanol (1-butanol) used as thewetting fluid can comprise, for example, from about 1% to about 33%,more narrowly about 9% by weight of the total weight of the solution.N-butyl acetate used as the wetting fluid can comprise, for example,from about 1% to about 34%, more narrowly about 14% by weight of thetotal weight of the solution. Dimethyl acetamide used as the wettingfluid can comprise, for example, from about 1% to about 40%, morenarrowly about 20% by weight of the total weight of the solution.

In accordance with one embodiment, the microparticles 20 are embeddedwithin the polymer solution 18, thereby forming a polymer matrix thatsecurely adheres to the surface of stent 10. In addition, depending onthe polymer solution 18 and the porosity of the micro/nano-spheres 20,the drug release rates may also be controlled. With the use of a polymersolution 18, such as ethylene vinyl alcohol copolymer, polycaprolactone,poly(lactide-co-glycolide), poly(hydroxybutyrate), and the like, thedeposited polymer solution 18 should be exposed to a heat treatment attemperature range greater than about the glass transition temperature(Tg) and less than about the melting temperature (Tm) of the polymer.Stent 10 should be exposed to the heat treatment for any suitableduration of time, which would allow for the formation of the coating onthe surface of stent 10 and allows for the evaporation of the solvent orcombination of solvent and wetting fluid, if necessary. It is understoodthat essentially all of the solvent and the wetting fluid will beremoved from the composition but traces or residues can remain blendedwith the polymer. The Tg and Tm for the polymers used in the embodimentsof the present invention are attainable by one or ordinary skill in theart.

Table 1 lists the T_(g) and T_(m) for some exemplary polymers which canbe used in embodiments of the present invention. T_(g) and T_(m) ofpolymers are attainable by one or ordinary skill in the art. The citedexemplary temperature and time for exposure is provided by way ofillustration and it is not meant to be limiting.

TABLE 1 Exemplary Exemplary Duration of Temperature Time For PolymerT_(g) (° C.) Tm (° C.) (° C.) Heating EVOH 55 165 140 4 hourspolycaprolactone −60 60 50 2 hours ethylene vinyl 36 63 45 2 hoursacetate (e.g., 33% vinylacetate content) Polyvinyl 75-85* 200-220* 165 2hours alcohol *Exact temperature depends on the degree of hydrolysiswhich is also known as the amount of residual acetate.

With the use of one of the aforementioned thermoplastic polymers, theuse of initiators may be required. By way of example, epoxy systemsconsisting of diglycidyl ether of bisphenol A resins can be cured withamine curatives, thermoset polyurethane prepolymers can cured withpolyols, polyamines, or water (moisture), and acrylated urethane can becured with UV light. Further discussion of polymers, solvents, wettingfluids and initiators are disclosed in commonly assigned U.S.application Ser. No. 09/750,595, now U.S. Pat No. 6,730,288, entitled“Coating for Implantable Devices and a Method of Forming the Same”,filed Dec. 28, 2000, which is herein incorporated by reference for allpurposes.

The following methods may be used to embed the micro/nano-spheres 20 inthe polymer solution 18 and apply the resulting matrix to the surface ofstent 10. Although several methods are disclosed, it is to be understoodthat the following list is not inclusive. Other similar methods may alsobe used and are within the scope of the presently claimed invention.

Method 1

EVOH Solution Formulation: An EVOH solution is made by adding 10 gramsof EVOH into 90 grams of DMAC. The components are dissolved to form asolution by heating the mixture to 50° C., with constant stirring.

Stent Coating Process: PEGDA microparticles 20, ranging in size fromapproximately 0.5 to 2.0 microns (0.1×10⁻⁴ mm to 0.5×10⁻⁴ mm) in length,are suspended in the EVOH solution by adding 20 grams of microparticles20 into 80 grams of the EVOH solution. The final suspension isconstantly agitated or stirred to prevent flocculation. Stents 10 aredipped in the final suspension and then centrifuged at 6,000 rpm for 60seconds resulting in a coating having a relatively smooth surfacetexture.

Method 2

EVOH Solution Formulation: see Method 1 (above).

Stent Coating Process: see Method 1 (above). In addition, a co-solventsolution is formulated by combining 2% EVOH in 1:1 w/w DMSO:DMF. Stents10 are then spray-coated with a top coat of a co-solvent solution sothat the initial microparticle 20 coating is completely covered by theEVOH top coat. This top coat provides a means to control drug releaserates and obtain smooth surface textures.

Method 3

EVOH Solution Formulation: see Method 1 (above).

Stent Coating Process: Ac/D loaded CAP microparticles 20, ranging insize from approximately 0.5 to 2.0 microns (0.1×10⁻⁴ mm to 0.5×10⁻⁴ mm)in length, are suspended in the EVOH solution by adding 20 grams ofmicroparticles to 80 grams of EVOH solution. To prevent flocculation,the final solution is constantly stirred. Stents 10 are then dipped inthe final suspension and then centrifuged at 6,000 rpm for 60 seconds,resulting in a coating having a relatively smooth surface texture. Thecoated stents 10 are then spray-coated with a top coat of a co-solventsolution containing 2% EVOH in DMAC. This top coat provides a means tocontrol drug release rates and obtain smooth surface textures.

Method 4

EVOH Solution Formulation: see Method 1 (above). Prior to applying thepolymer matrix, described below, stents 10 are initially coated with alayer of EVOH by dipping, spraying or similar coating techniques.

Stent Coating Process: PEGDA microparticles 20, ranging in size fromapproximately 0.5 to 2.0 microns (0.1×10⁻⁴ mm to 0.5×10⁻⁴ mm) in length,are suspended in methanol by adding 50 grams of microparticles 20 into50 grams of methanol. The final suspension (i.e. polymer matrix) isconstantly stirred to prevent flocculation. Stents 10 are dipped in thefinal suspension and then centrifuged at 2,000 rpm for 60 secondsresulting in a coating having a relatively smooth surface texture. Thecoated stents 10 are then spray-coated with a co-solvent solutioncontaining 2% EVOH in 1:1 w/w DMSO:DMF.

Method 5

EVOH Solution Formulation: see Method 4 (above).

Stent Coating Process: PEGDA microparticles 20, ranging in size fromapproximately 0.5 to 2.0 microns (0.1×10⁻⁴ mm to 0.5×10⁻⁴ mm) in length,are suspended in methanol by adding 50 grams of microparticles 20 into50 grams of methanol. The final suspension is constantly stirred toprevent flocculation. Stents 10 are selectively dipped, e.g. only theends 14, 16 of each stent 10 are dipped, in the final suspension andthen centrifuged at 1,000 rpm for 30 seconds resulting in a coatinghaving a relatively smooth surface texture. The coated stents 10 arethen spray-coated with a top coat of a co-solvent solution containing 2%EVOH in 1:1 w/w DMSO:DMF. The initial selective dipping of stent 10,together with the sprayed top-coat, produces a hydrogel cushion at eachend 14, 16 of stent 10. This hydrogel cushion reduces or eliminatestrauma to the lumen or vessel due to contact with un-coated ends 14, 16of stent 10.

Method 6

EVOH Solution Formulation: see Method 4 (above).

Stent Coating Process: VP microparticles 20, ranging in size fromapproximately 0.5 to 2.0 microns (0.1×10⁻⁴ mm to 0.5×10⁻⁴ mm) in length,are suspended in methanol by adding 50 grams of microparticles 20 into50 grams of methanol. The final suspension is constantly stirred toprevent flocculation. Stents 10 are dipped in the final suspension andthen centrifuged at 2,000 rpm for 60 seconds resulting in a coatinghaving a relatively smooth surface texture. The coated stents 10 arethen spray-coated with a co-solvent solution containing 2% EVOH in 1:1w/w DMSO:DMF, thereby completely covering the microparticle 20 coatingwith a top-coat of EVOH.

Alternative methods of applying drug-loaded microparticles 20 onto thesurface of a stent 10, including various combinations of methods, arealso within the scope of the present disclosure. The type ofmicroparticle 20, drug and layering technique provide increased volumeof drug-loading on stent 10 and controllable drug release rates. Forexample, in one embodiment, the entire stent 10 is coated with a firstlayer of EVOH as described above. A first suspension of Ac/D loaded CAPmicroparticles 20 and a second suspension of PEGDA microparticles 20(formulated according to the methods described above) are selectivelyapplied as a second layer on stent 10. In particular, the first end ofstent 10 is coated with a layer of the first suspension and the secondend 16 of stent 10 is coated with a layer of the second suspension. Thisembodiment allows stent 10 to selectively deliver two types of drugs totwo different target sites in the lumen.

In an alternate embodiment, the entire stent 10 is coated with a firstlayer of EVOH. A suspension made of a combination of Ac/D loaded CAPmicroparticles 20 and PEGDA microparticles 20 is formulated and appliedas a second layer on stent 10. The ratio of Ac/D loaded CAPmicroparticles 20 to PEGDA microparticles 20 in the suspension isvariable based upon the desired treatment or diagnosis. In addition, thesecond layer of the suspension may either be applied over the entirestent 10 or over only selective portions of stent 10, using dipping,spraying, or other similar methods.

In yet another embodiment, the entire stent 10 is coated with a firstlayer of EVOH. A second layer comprising a suspension formulated from acombination of Ac/D loaded CAP microparticles 20, PEGDA microparticles20 and VP microparticles 20 is selectively applied to stent 10.Alternatively, only selected portions of stent 10 may be coated with avariety of second layers. For example, a first portion of stent 10 maybe coated with a suspension consisting of Ac/D loaded CAP microparticles20 and VP microparticles 20, a second portion with only PEGDAmicroparticles 20, and a third portion with PEGDA microparticles 20 andVP microparticles 20.

In yet another embodiment, microparticles 20 can be layered bydepositing a first layer followed by a top-coating. The top-coating canbe, for example, a blank matrix polymer. A second layering ofmicroparticle 20 can then be applied over the top-coating. In oneembodiment, the second layering of microparticles 20 can be the sametype of microparticles as the first layering or, alternatively, thesecond layering can include a different type of microparticles 20 (i.e.,a different formulation) from the first layering of microparticles 20.The process of layering microparticles intermittent with the top-coatingcan be repeated to provide layering patterns according to therequirements of the desired treatment or diagnosis.

Embodiments of the device make possible site specific treatmenttherapies. Coating different portions of a stent, or other implantablemedical device, with the disclosed microparticles loaded with variousdrugs advantageously allows site-specific treatment of discrete sectionsof the patient's lumen. In addition, by embedding the drug-loadedmicroparticle in a polymer, the resulting matrix can increase ordecrease the release rate of the drug from the microparticle, dependingon the type of polymer used. As such, drug release rates and, forexample, long term treatment or diagnostic capabilities, can becontrolled.

The scope of the present invention also includes alternative stentembodiments having various combinations of drugs and layeringpatterns/methods. The particular drug(s) and layering patterns on thestent are configured according to the requirements of the desiredtreatment or diagnosis.

Although the invention has been described in terms of particularembodiments and applications, one of ordinary sill in the art, in lightof this teaching, can generate additional embodiments and modificationswithout departing from the spirit of or exceeding the scope of theclaimed invention. Accordingly, it is to be understood that the drawingsand descriptions herein are proffered by was of example to facilitatecomprehension of the invention and should not be construed to limit thescope thereof.

1. A method of coating a stent comprising: adding polymeric particlescontaining a therapeutic substance to a fluid form of a stent coatingmaterial, wherein the coating material comprises a polymeric materialdissolved in a solvent, such that the polymeric particles containing thetherapeutic substance are suspended in the coating material; applyingthe fluid form of the coating material comprising the polymericparticles added thereto to a stent; and solidifying the coating materialto a film layer by allowing the solvent to evaporate, wherein the filmlayer comprises the polymeric particles containing the therapeuticsubstance.
 2. The method of claim 1, wherein the polymeric particles aremade by water-in-oil emulsion.
 3. The method of claim 1, wherein thepolymeric particles have a hydrogel consistency.
 4. The method of claim1, wherein the therapeutic substance is for the treatment of restenosis.5. The method of claim 1, wherein the film layer comprises the polymericmaterial encasing the polymeric particles.
 6. The method of claim 1,wherein the polymeric material dissolved in the solvent is selected fromthe group consisting of polyvinyl alcohol, ethylene-vinyl alcoholcopolymers, polyurethanes, and copolymers and mixtures thereof.
 7. Themethod of claim 6, wherein the polymeric material dissolved in thesolvent is a polyurethane.
 8. The method of claim 6, wherein thepolymeric material dissolved in the solvent is polyvinyl alcohol.
 9. Themethod of claim 6, wherein the polymeric material dissolved in thesolvent is an ethylene-vinyl alcohol copolymer.
 10. The method of claim1, wherein the coating material further comprises a second therapeuticsubstance that may be the same as or different from the therapeuticsubstance of the polymeric particles.
 11. The method of claim 1, whereina polymer of the polymeric particles is different from the polymericmaterial of the coating material.
 12. The method of claim 1, wherein thecoating material is free from any therapeutic substances.
 13. The methodof claim 1, wherein the film layer is free from any therapeuticsubstances such that the therapeutic substance is encased only in thepolymeric particles.
 14. The method of claim 13, wherein a polymer ofthe polymeric particles is different from the polymeric material of thecoating material.
 15. The method of claim 1, wherein the polymericparticles comprise a polymer, the constituent monomer of the polymer orat least one constituent monomer of the polymer being vinyl pyrrolidone.16. The method of claim 1, wherein the polymeric particles comprise apolymer, the constituent monomer of the polymer or at least oneconstituent monomer of the polymer being polyethylene glycol diacrylate.17. The method of claim 1, wherein the polymeric particles comprisepoly(alginate).
 18. The method of claim 1, wherein the polymericparticles comprise cellulose acetate phthalate.